ABSTRACT This project will test whether sleep consolidation is an effective modulator of the progression of Alzheimer's disease. Sleep disturbances are increasingly recognized as a major correlate of neurodegenerative disorders, including Alzheimer's disease (AD). Experimental studies in rodent models of AD have established that insufficient sleep per se accelerates the course of disease progression. We have found that sleep disruption, especially in aged animal models, is associated with cellular protein dyshomeostasis. Most neurodegenerative diseases such as Alzheimer's disease are characterized by the accumulation of protein aggregates which are indicative of severe protein dyshomeostasis in the brain. Interventions aimed at improving homeostatic protein regulation in the cell have been found to be efficacious in reducing AD symptoms in animal models of the disease. The chemical chaperone 4-phenylbuyrate (PBA) has also been demonstrated to reduce plaque number in a mouse model of AD. PBA has previously been shown to extend lifespan in wildtype Drosophila and we have also demonstrated that it restores protein homeostasis and rescues age-related sleep fragmentation in Drosophila. Taken together these data suggest that improvements in sleep may underlie some of the therapeutic benefits of PBA. To address this possibility, we conducted a lifespan assay of wildtype flies treated with the pharmacological somnogen Zolpidem. Zolpidem administration consolidates sleep and also led to treated flies living longer, recapitulating the lifespan extension observed with PBA treatment. To our knowledge, this is the first evidence that a commonly-used sleep-modifying agent can improve aging. Based on these preliminary findings, we hypothesize that consolidating sleep using pharmacological somnogens will extend lifespan, improve AD-related behaviors, and ultimately delay the progression of amyloid- mediated neurodegeneration in a Drosophila model of AD. Thus, we propose testing the efficacy of the sedative-hypnotic Zolpidem and the chemical chaperone PBA, which are both FDA approved drugs, for improving sleep, cognitive behavior, progression of disease pathogenesis and lifespan in the Drosophila A?42 arctic (A?42arc) model of Alzheimer's disease. We expect the interventions will ameliorate sleep consolidation and protein homeostasis in this AD model, and delay disease progression, improve cognitive behavior and extend lifespan. The results of this study will not only provide information about potential AD therapies, but will also offer greater insight into the relationship between sleep and neurodegeneration, both of which remain poorly understood phenomena of the human brain.